WO2018181820A1

WO2018181820A1 - Heterocyclic compound

Info

Publication number: WO2018181820A1
Application number: PCT/JP2018/013469
Authority: WO
Inventors: 伸之松永; 藤本　卓也; 潤藤本; 幸恵森本; 広行筧; 松尾　孝徳; 暢村木; 貴子内藤; 珠蘭加藤; 洋長袋; 泰徳仁尾; 賦大川原; 俊太郎土屋
Original assignee: 武田薬品工業株式会社
Priority date: 2017-03-31
Filing date: 2018-03-29
Publication date: 2018-10-04
Also published as: JP2020097527A

Abstract

The present invention relates to a compound that can be effective for prevention and/or treatment of pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin, or heart, non-alcoholic steatohepatitis, diabetic nephropathy, and the like. A compound, or a salt thereof, selected from: 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-N-{4-[(N,N-dimethylglycyl)amino]cyclohexyl}-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide; 4-(5-(difluoromethyl)-2-{[1-(difluoromethyl)cyclopropyl]methoxy}phenyl)-6-methyl-N-[4-(propionylamino)cyclohexyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide; and 4-{2-[(3-fluoropyridine-2-yl)methoxy]-5-(trifluoromethyl)phenyl}-6-methyl-N-[4-(propionylamino)cyclohexyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide.

Description

Heterocyclic compounds

The present invention relates to phosphodiesterase (PDE) inhibition that may be useful for the prevention and / or treatment of pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin or heart, nonalcoholic steatohepatitis, diabetic nephropathy and the like. The present invention relates to a novel compound that can have an action.

(Background of the Invention)
Pulmonary hypertension is a disease with an extremely poor prognosis, in which pulmonary vascular resistance increases due to abnormal proliferation, remodeling, contraction, etc. of the myocardium and pulmonary vascular tissue, leading to death due to heart failure as the disease progresses. Pulmonary hypertension is mainly classified into five groups according to the onset mechanism. The first group is pulmonary arterial pulmonary hypertension, the second group is pulmonary hypertension associated with left heart disease, and the third group is Pulmonary hypertension associated with pulmonary disease and / or hypoxemia, group 4 includes chronic thromboembolic pulmonary hypertension, group 5 includes pulmonary hypertension associated with multi-factor mechanisms of unknown details, etc. Are classified respectively. The main therapeutic agents currently used are endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogs, soluble guanylate cyclase (sGC) stimulators, etc., although some symptoms are improved, but still Prognosis is bad. In recent years, it has become clear that multiple molecules are involved in the pathology of the disease, and current therapeutic agents have limited effects with single agents, so the development of new therapeutic agents is desired . In particular, pulmonary arterial hypertension associated with connective tissue disease in the first group and pulmonary hypertension in the third group have advanced fibrosis and poor prognosis, and the development of new therapeutic agents is required. Yes.
Pulmonary fibrosis, represented by interstitial lung disease, is caused by alveolar epithelial cell damage resulting in excessive production of extracellular matrix components, resulting in alveolar stroma fibrosis and respiratory function. It is known as a fatal disease that decreases. Interstitial lung disease is mainly classified into 9 categories: 1) idiopathic interstitial pneumonia of unknown cause, 2) lung disease of collagen disease and related diseases, 3) drug-induced lung disease, 4) neoplastic lung Diseases are included.
Idiopathic Pulmonary Fibrosis (IPF) is the result of excessive production of extracellular matrix components due to the failure of alveolar epithelial cells, resulting in advanced fibrosis of the alveolar stroma and respiratory It is known as a fatal disease with reduced function. Spotted fibrosis is observed, many fibroblast nests are observed, and in high-resolution tomography (HRCT), the fibrotic and thickened septum is seen as honeycomb lungs, and findings with traction bronchodilation are obtained. Symptoms include dry cough and shortness of breath during exertion, resulting in difficulty breathing. The prognosis from the initial diagnosis is very poor, and the survival rate after 5 years is said to be about 50%. Steroids and immunosuppressants are ineffective, and antifibrotic drugs such as pirfenidone have recently been used clinically, but their therapeutic effects have been limited to a limited level. Side effects and phototoxicity problems have been pointed out. In patients with pulmonary fibrosis, pulmonary hypertension is accompanied by vascular remodeling. Prognosis is poor when patients with pulmonary fibrosis are complicated by pulmonary hypertension. Existing pulmonary vasodilators such as endothelin receptor antagonists have no effect on pulmonary hypertension associated with pulmonary fibrosis, and development of new therapeutic agents is required.
As pyrrolopyrimidine derivatives having a PDE inhibitory action, for example, compounds described in Patent Document 1 and Patent Document 2 are known.

International Publication WO2011 / 023693 International Publication No. WO2009 / 106531

Development of a compound that is useful as a preventive and / or therapeutic agent for pulmonary hypertension, pulmonary fibrosis, etc. and has excellent properties in terms of drug efficacy, low toxicity, stability, pharmacokinetics, and the like is desired.
The present invention provides a compound that inhibits PDE (especially PDE4 and PDE5) having a chemical structure different from that of known compounds, and a preventive and / or therapeutic agent for pulmonary hypertension, pulmonary fibrosis and the like comprising the compound. For the purpose.
The present invention also relates to a compound that inhibits PDE (especially PDE4 and PDE5) having a chemical structure different from that of a known compound, and fibrosis in the liver, kidney, skin or heart, non-alcoholic steatohepatitis comprising the compound Another object is to provide a preventive and / or therapeutic drug for diabetic nephropathy and the like.

As a result of extensive research, the present inventors have synthesized the following compound for the first time, and found that this compound can have an unexpectedly excellent PDE (particularly PDE4 and PDE5) inhibitory action, thereby completing the present invention. It came to do.

That is, the present invention
[1] 4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxamide;
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide; and
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3 , 2-d] pyrimidine-7-carboxamide or a salt thereof;
[2] 4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {trans-4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H -Pyrrolo [3,2-d] pyrimidine-7-carboxamide;
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide; and
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [3,2-d] pyrimidine-7-carboxamide compound or salt thereof according to [1] or a salt thereof;
[3] A medicament comprising the compound or salt thereof according to [1];
[4] The pharmaceutical according to [3], which is a PDE4 / 5 inhibitor (PDE4 and / or PDE5 inhibitor);
[5] The medicament according to [3], which is a preventive or therapeutic agent for pulmonary hypertension and / or pulmonary fibrosis;
[6] The medicament according to [3], which is a preventive or therapeutic agent for nonalcoholic steatohepatitis and / or diabetic nephropathy;
[7] The medicament according to [3], which is a prophylactic or therapeutic agent for fibrosis in the liver, kidney, skin or heart;
[8] The compound or salt thereof according to [1] for use in the prevention or treatment of pulmonary hypertension and / or pulmonary fibrosis;
[9] The compound or salt thereof according to [1] for use in the prevention or treatment of nonalcoholic steatohepatitis and / or diabetic nephropathy;
[10] The compound or salt thereof according to [1] for use in the prevention or treatment of fibrosis in the liver, kidney, skin or heart;
[11] A method for inhibiting PDE4 / 5 in a mammal (PDE4 and / or PDE5 inhibition method), which comprises administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[12] A method for preventing or treating pulmonary hypertension and / or pulmonary fibrosis in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[13] A method for preventing or treating nonalcoholic steatohepatitis and / or diabetic nephropathy in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[14] A method for preventing or treating fibrosis in the liver, kidney, skin or heart of a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[15] Use of the compound or salt thereof according to [1] for producing a preventive or therapeutic agent for pulmonary hypertension and / or pulmonary fibrosis;
[16] Use of the compound or salt thereof according to [1] for producing a prophylactic or therapeutic drug for nonalcoholic steatohepatitis and / or diabetic nephropathy;
[17] Use of the compound or a salt thereof according to [1] for producing a prophylactic or therapeutic agent for fibrosis in the liver, kidney, skin or heart;
And so on.

The compound of the present invention may have an excellent PDE (particularly PDE4 and / or PDE5) inhibitory action, including pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin or heart, nonalcoholic steatohepatitis, diabetic It may be useful as a preventive and / or therapeutic agent for nephropathy and the like.

FIG. 3 is a diagram showing the action of the compounds of Example 1, Example 2 and Example 3 on type 1 collagen expression (mean ± standard deviation n = 3). It is a figure which shows the right ventricular hypertrophy improvement effect of the compound of Example 1, Example 2 and Example 3 in a monocrotaline pulmonary hypertension model (mean ± standard deviation n = 4-12 #: p ≦ 0.05 vs. vehicle by Williams' test mpk, mg / kg).

(Detailed description of the invention)
The present invention is described in detail below.
The compound of the present invention
4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide or a salt thereof;
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide or a salt thereof; and
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3 , 2-d] pyrimidine-7-carboxamide or a salt thereof.

More specifically, the compound of the present invention is
4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {trans-4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide or a salt thereof;
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide or a salt thereof; and
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [3,2-d] pyrimidine-7-carboxamide or a salt thereof.

The compound of the present invention is produced by the method described in the examples.

The salt in the compound of the present invention is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid. Salts, salts with basic or acidic amino acids are mentioned.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt.
Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

The compound of the present invention may have a PDE (particularly PDE4 and / or PDE5) inhibitory action.
The compound of the present invention may have low toxicity, and based on PDE (particularly PDE4 and / or PDE5) inhibitory action, mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, Pulmonary hypertension (Pulmonary Arterial Hypertension (PAH)), Group 1 'pulmonary vein occlusive disease (PVOD) and / or pulmonary capillary hemangiomatosis (dogs, sheep, goats, etc.) PCH), pulmonary hypertension associated with group 2 left heart disease, pulmonary hypertension associated with group 3 pulmonary disease and / or hypoxemia, group 4 chronic thromboembolic pulmonary hypertension (CTEPH), Pulmonary hypertension associated with multi-factor mechanisms of unknown group details), pulmonary fibrosis (Idiopathic Pulmonary Fibrosis (IPF)), lung pathology of collagen disease and related diseases, drug-induced lung disease, occupation Sexual / environmental lung disease, neoplastic lung disease, infection-related lung disease, etc.) It may be useful as a safe medicament explosion and / or treatment. Furthermore, based on the inhibitory action on both PDE4 and PDE5, the prognosis can be improved in patients with pulmonary hypertension with fibrotic lesions and in patients with pulmonary fibrosis based on both effects of improving fibrosis and reducing pulmonary artery pressure. Be expected. It is also expected to be useful for the prevention and / or treatment of fibrosis in the liver, kidney, skin or heart.
Furthermore, the compound of the present invention is expected to be useful for the prevention and / or treatment of nonalcoholic steatohepatitis and diabetic nephropathy.

The compound of the present invention can be expected to have low toxicity (for example, it should be superior as a pharmaceutical in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.) As mammals (for example, humans) as pharmaceuticals as they are, or as pharmaceutical compositions (sometimes referred to herein as “medicaments of the present invention”) mixed with a pharmaceutically acceptable carrier or the like , Monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) and can be safely administered orally or parenterally. “Parenteral administration” includes intravenous, intramuscular, subcutaneous, intraorgan, intrapulmonary, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. Administration and direct administration to the lesion.

The dose of the compound of the present invention may vary depending on the administration route and symptoms. For example, when orally administered to a patient with pulmonary hypertension and / or pulmonary fibrosis (adult, body weight 40 to 80 kg, eg 60 kg), for example, about 0.001 to about 1000 mg / kg body weight per day, preferably about 0 per day 0.01 to about 100 mg / kg body weight, more preferably about 0.1 to about 10 mg / kg body weight per day. This amount may be administered in 1 to 3 divided doses per day.

The pharmaceutical dosage form of the present invention includes tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, film-forms (eg , Orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion Oral, parenteral preparations such as suppositories, patches, suppositories (eg, rectal suppositories, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. These can be safely administered orally or parenterally. It can be.

Examples of the “pharmaceutically acceptable carrier” include various organic or inorganic carriers conventionally used as starting materials. For example, solid preparations include excipients, lubricants, binders, disintegrants, etc., and liquid preparations include solvents, solubilizers, suspending agents, isotonic agents, buffering agents, painlessness. And the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be used.

Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.

Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.

Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

Suitable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate and citrate.

Benzyl alcohol is a preferred example of the soothing agent.

Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

Preferable examples of the antioxidant include sulfite and ascorbate.

Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, β-carotene, chlorophyll, bengara).

Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.

The medicament of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.

The content of the compound of the present invention in the medicament of the present invention varies depending on the dosage form, administration method, carrier and the like. , Preferably about 0.1 to about 95% (w / w). The medicament of the present invention can be produced according to a conventional method by adding the compound of the present invention in such a ratio.

The compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).

Examples of the concomitant drug include pirfenidone used for idiopathic pulmonary fibrosis, sildenafil which is a PDE5 inhibitor, and the like.

Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents. Thus, the adverse effects that would be caused by these agents can be safely prevented.

By combining the compound of the present invention and a concomitant drug,
(1) Compared with the case where the compound of the present invention or the concomitant drug is administered alone, the dose can be reduced.
(2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with the compound of the present invention can be selected.
(3) The treatment period can be set longer by selecting a concomitant drug having a different mechanism of action from the compound of the present invention.
(4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained.
(5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be expected.

Hereinafter, the combined use of the compound of the present invention and the concomitant drug is referred to as “the combination agent of the present invention”.
In the use of the concomitant drug of the present invention, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to the administration subject. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
The administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) formulating the compound of the present invention and the concomitant drug separately. Simultaneous administration of the two obtained preparations by the same administration route, (3) administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different times in the same administration route, (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Obtained by separately formulating the compound of the present invention and a concomitant drug 2 Administration of different preparations at different time intervals (for example, the compound of the present invention; administration in the order of concomitant drugs, or administration in the reverse order).

The concomitant drug of the present invention can be expected to have low toxicity. For example, the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, For example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical , Rectal, intravenous administration, etc.). An injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly into a lesion.
Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as a pharmaceutical material. For example, for solid preparations, excipients, lubricants, binders, disintegrants and the like can be mentioned. Liquid preparations include solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. Further, if necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation. For example, it is about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight based on the whole preparation. % By weight, more preferably about 0.5 to about 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, for example, about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to about 20% by weight.
The content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation. For example, it is about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight based on the whole preparation. Degree.
The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.

The present invention is further explained in detail by the following examples, experimental examples and formulation examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
“Room temperature” in the following examples usually indicates about 10 ° C. to about 35 ° C. The ratio shown in the mixed solvent is a volume ratio unless otherwise specified. Unless otherwise indicated, “%” indicates “% by weight”.
Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, using 60 _{F 254} Merck (Merck) manufactured as a TLC plate, was used as a developing solvent, the solvent used as an elution solvent in column chromatography. A UV detector was used for detection. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when NH was described, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when Diol was described. In preparative HPLC (high performance liquid chromatography), when it was described as C18, octadecyl bonded silica gel was used. The ratio shown in the elution solvent indicates a volume ratio unless otherwise specified.
^For the analysis of ¹ H NMR, ACD / SpecManager (trade name) software or the like was used. Peaks with very gentle proton peaks such as hydroxyl groups and amino groups may not be described.
MS was measured by LC / MS. As the ionization method, an ESI method or an APCI method was used. The data shows actual values (found). Usually, a molecular ion peak is observed, but it may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.

The following abbreviations are used in the following examples.
MS: Mass spectrum
CDCl ₃ : Deuterated chloroform
DMSO-d _6: deuterated dimethyl sulfoxide
¹ H NMR: proton nuclear magnetic resonance
ESI: electrospray ionization
APCI ： atmospheric pressure chemical ionization
TFA: trifluoroacetic acid
IPE: Diisopropyl ether
n-BuLi: Butyllithium
DMF: N, N-dimethylformamide
HOBt: 1H-benzotriazol-1-ol
THF: tetrahydrofuran
WSC: N- (3- (dimethylamino) propyl) -N'-ethylcarbodiimide
WSC / HCl: N- (3- (Dimethylamino) propyl) -N'-ethylcarbodiimide hydrochloride
DMSO: Dimethyl sulfoxide
DAST: diethylaminosulfur trifluoride

Example 1
4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {trans-4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide

4- (2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl) -6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxylic acid (7.0 g), N- (trans- 4-aminocyclohexyl) -N ', N'-dimethylglycinamide (8.32 g), N, N-diisopropylethylamine (9.8 mL) and DMF (70 mL) in a mixture of WSC (5.39 g) and HOBt (2.53 g) Was added at room temperature and the mixture was stirred at room temperature overnight. A saturated aqueous sodium carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (5.2 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.24-0.29 (2H, m), 0.37-0.41 (2H, m), 0.94-0.99 (1H, m), 1.36-1.49 (4H, m), 1.77 -1.84 (2H, m), 1.99-2.05 (2H, m), 2.22 (6H, s), 2.79 (3H, s), 2.86 (2H, s), 3.66-3.68 (1H, m), 3.80-3.82 (1H, m), 3.96 (2H, d, J = 6.8 Hz), 6.95-7.23 (1H, m), 7.31 (1H, d, J = 8.8 Hz), 7.56 (1H, d, J = 8.4 Hz) , 7.74 (1H, d, J = 8.8 Hz), 7.83 (1H, d, J = 1.0 Hz), 8.65 (1H, d, J = 7.8 Hz), 8.99 (1H, s), 11.85 (1H, s) .

Example 2
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide

A) (1-{[2-Bromo-4- (difluoromethyl) phenoxy] methyl} cyclopropyl) methanol 2-bromo-4- (difluoromethyl) -1-fluorobenzene (19.18 g) and DMSO (192 ml) To this mixture, cyclopropane-1,1-diyldimethanol (16.35 ml) and cesium carbonate (41.7 g) were added at room temperature. The mixture was stirred at 76-78 ° C. for 22 hours. The mixture was diluted with ethyl acetate and water was added at room temperature. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (20.26 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.64-0.76 (4H, m), 2.18 (1H, t, J = 5.9 Hz), 3.69 (2H, d, J = 5.9 Hz), 4.03 (2H, s) , 6.34-6.79 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.67-7.75 (1H, m).

B) 1-{[2-Bromo-4- (difluoromethyl) phenoxy] methyl} cyclopropanecarbaldehyde (1-{[2-bromo-4- (difluoromethyl) phenoxy] methyl} cyclopropyl) methanol (13.31 g ) And acetonitrile (133 ml) were added Dess-Martin periodinane (19.30 g) at 0 ° C. The mixture was stirred at room temperature for 2 hours. To the mixture were added saturated aqueous sodium hydrogen carbonate solution and sodium carbonate (7.19 g) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (12.53 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32-1.40 (2H, m), 1.41-1.49 (2H, m), 4.36 (2H, s), 6.34-6.79 (1H, m), 6.99 (1H, d , J = 8.7 Hz), 7.41 (1H, d, J = 9.1 Hz), 7.69 (1H, s), 8.94 (1H, s).

C) 2-bromo-4- (difluoromethyl) -1-{[1- (difluoromethyl) cyclopropyl] methoxy} benzene 1-{[2-bromo-4- (difluoromethyl) phenoxy] methyl} cyclopropanecarba DAST (11.39 ml) was added to a mixture of aldehyde (12.52 g) and toluene (125 ml) at 1.5-2.5 ° C. The mixture was stirred at room temperature for 16 hours. The reaction solution was added dropwise to saturated aqueous sodium hydrogen carbonate solution at 4-10 ° C., and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (11.87 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.78-0.88 (2H, m), 0.97-1.06 (2H, m), 4.09 (2H, s), 5.83-6.29 (1H, m), 6.34-6.80 (1H , m), 6.89 (1H, d, J = 8.3 Hz), 7.41 (1H, d, J = 9.1 Hz), 7.70 (1H, s).

D) Ethyl 4- (5- (difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxy Lato 2-bromo-4- (difluoromethyl) -1-{[1- (difluoromethyl) cyclopropyl] methoxy} benzene (10.01 g) and THF (100 ml) in a mixture of triisopropyl borate (7.29 ml) and n -BuLi (1.6 M THF solution, 19.86 ml) was added at -78 ° C. The mixture was stirred at −78 ° C. for 30 minutes, slowly warmed to room temperature, and stirred at room temperature for 3 hours. To the reaction solution were added 2 M aqueous sodium carbonate solution (58.8 ml) and ethyl 4-chloro-6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxylate (5.64 g) at room temperature. Under a nitrogen atmosphere, bis (triphenylphosphine) palladium (II) dichloride (0.826 g) was added to the mixture, and the mixture was refluxed for 41 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, and water and saturated brine were added at room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the mixture was purified by silica gel column chromatography (NH, ethyl acetate). The residue was suspended in IPE, and the resulting precipitate was collected by filtration. The obtained solid was washed with IPE to give the title compound (7.75 g).
MS: [M + H] ⁺ 452.2.

E) 4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxylic acid Ethyl 4- (5- (difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxylate ( To a mixture of 15.00 g), tert-butanol (150 ml) and water (1.5 ml) was added potassium tert-butoxide (18.64 g) at room temperature. The mixture was stirred at 85 ° C. for 14 hours. Water (300 ml) was added to the mixture at 30-32 ° C. Activated carbon (1.40 g) was added to the mixture and stirred at 28-32 ° C. for 1 hour. The reaction solution was filtered, the filtrate was acidified (pH = 3-4) with 2 M aqueous citric acid solution (66.46 ml), and the mixture was stirred at 26 ° C. for 1 hour. The resulting solid was collected by filtration and washed with water to give the title compound (13.84 g).
MS: [M + H] ⁺ 424.1.

F) 4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H- Pyrrolo [3,2-d] pyrimidine-7-carboxamide 4- (5- (difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-5H-pyrrolo [3 , 2-d] pyrimidine-7-carboxylic acid (13.50 g) and DMF (135 ml) were mixed with N- (trans-4-aminocyclohexyl) propanamide hydrochloride (8.57 g) and 1H-benzotriazole-1- All monohydrate (7.32 g), WSC · HCl (9.17 g) and triethylamine (13.33 ml) were added at 27-37 ° C. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, and water and saturated aqueous sodium hydrogen carbonate solution were added at room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in isopropyl acetate, and the resulting precipitate was collected by filtration. The obtained solid was washed with isopropyl acetate to give the title compound (18.31 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.62 (2H, brs), 0.79-0.90 (2H, m), 1.12-1.19 (3H, m), 1.28-1.42 (2H, m), 1.46-1.68 (2H , m), 2.06-2.25 (6H, m), 2.91 (3H, s), 3.77-4.08 (2H, m), 4.20 (2H, s), 5.21-5.65 (2H, m), 6.50-6.91 (1H , m), 7.21 (1H, d, J = 8.7 Hz), 7.70 (1H, d, J = 9.8 Hz), 8.13 (1H, s), 8.91 (1H, d, J = 7.6 Hz), 9.07 (2H , s).

Example 3
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [3,2-d] pyrimidine-7-carboxamide

A) 4- [2-Hydroxy-5- (trifluoromethyl) phenyl] -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [3,2-d] pyrimidine-7 -Carboxamide 4- [2- (Cyclopropylmethoxy) -5- (trifluoromethyl) phenyl] -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [3,2-d A mixture of pyrimidine-7-carboxamide (3.0 g) and TFA (20 ml) was stirred at 80 ° C. overnight. The reaction mixture was concentrated, and the resulting residue was washed with IPE to give the title compound (3.18 g).
MS: [M + H] ⁺ 490.3.

B) 4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H -Pyrrolo [3,2-d] pyrimidine-7-carboxamide 4- [2-hydroxy-5- (trifluoromethyl) phenyl] -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H (3-Fluoropyridin-2-yl) methanol (2.142 g) and triphenylphosphine (5.89 g) in a mixture of 2-pyrrolo [3,2-d] pyrimidine-7-carboxamide (2.75 g) and THF (75 ml) And di-tert-butyl diazenedicarboxylate (5.17 g) were added at room temperature. The mixture was stirred at 60 ° C. for 16 hours under a nitrogen atmosphere. Water was added to the mixture and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The obtained solid was crystallized from ethanol / hexane to give the title compound (2.42 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17 (3H, t, J = 7.6 Hz), 1.30-1.44 (2H, m), 1.50-1.56 (1H, m), 1.60 (1H, brs), 2.06- 2.25 (6H, m), 2.91 (3H, s), 3.77-3.95 (1H, m), 3.97-4.11 (1H, m), 5.28 (1H, d, J = 7.9 Hz), 5.61 (2H, s) , 6.87 (1H, d, J = 8.7 Hz), 7.42-7.51 (1H, m), 7.58 (1H, dd, J = 9.2, 2.4 Hz), 7.62-7.70 (1H, m), 8.17 (1H, d , J = 1.7 Hz), 8.52 (1H, d, J = 4.7 Hz), 8.92 (1H, d, J = 7.7 Hz), 9.08 (1H, s), 12.43 (1H, brs).

Example compounds are shown in Table 1 below. MS in the table indicates actual measurement.

Formulation Example A preparation containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
1. Capsule (1) 10 mg of the compound of Example 1
(2) Lactose 90mg
(3) Microcrystalline cellulose 70mg
(4) Magnesium stearate 10mg
1 capsule 180mg
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
2. Tablet (1) Compound of Example 1 10 mg
(2) Lactose 35mg
(3) Corn starch 150mg
(4) Microcrystalline cellulose 30mg
(5) Magnesium stearate 5mg
1 tablet 230mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
3. Injection (1) 10 mg of the compound of Example 1
(2) Inosit 100mg
(3) Benzyl alcohol 20mg
1 ampoule 130mg
Dissolve (1), (2), and (3) in distilled water for injection so that the total amount is 2 ml, and enclose it in an ampoule. All steps are performed under aseptic conditions.

Example 1
Inhibitory activity was evaluated using PDE4B, PDE4D and PDE5A proteins (BPS Bioscience) produced in Sf9 cells. Assay buffer (50 mM Tris-HCl, 8.3 mM MgCl ₂ , 1.7 mM EGTA, 0.1%) containing each PDE in Example 1, Example 2 and Example 3 (10 ⁻¹² −10 ⁻⁵ M) or solvent BSA) for 30 minutes, then [ ³ H] -labeled cAMP or cGMP (PerkinElmer) was added for 60 minutes and PDE4 and 5 inhibitory activity was assessed as radioactivity using a scintillation counter (PerkinElmer) . Based on the inhibitory activity at each concentration, the 50% inhibitory concentration (IC ₅₀ ) value (M) was calculated. The IC ₅₀ values for PDE4B, PDE4D and PDE5A in each example are shown in Table 2.

Experimental example 2
WI-38 human-derived fibroblasts were seeded on a 24-well plate at a density of 0.5 × 10 ⁵ cells / well and cultured for 24 hours. Thereafter, the compounds of Example 1, Example 2 and Example 3 were treated with 0.001 to 10 μM in the presence of TGFβ (3 ng / mL) and forskolin (1 μM) that promotes cAMP production. The effect on the gene expression of type 1 collagen (Col1a1), a fibrosis marker extracted and induced by TGF-β, was evaluated.
The compounds of Example 1, Example 2 and Example 3 suppressed collagen gene expression induced by TGFβ in a dose-dependent manner (FIG. 1).

Experimental Example 3
Monocrotaline was administered subcutaneously to Wistar rat (CLEA Japan) at 60 mg / kg to create a pulmonary hypertension model. From 1 week after induction of the disease state, the compound of Example 1, the compound of Example 2 and the compound of Example 3 were orally administered by gavage for a period of 2 weeks. After that, the weight ratio of the right ventricle to the left ventricle and septum (LV / RV + S) was calculated as an index of the improvement effect of right ventricular hypertrophy based on pulmonary artery pressure improvement. The right ventricular hypertrophy induced by the monocrotaline model was suppressed by the compounds of Example 1, Example 2 and Example 3 at a dose of 3 mg / kg (FIG. 2).

According to the present invention, it may have an excellent PDE (particularly PDE4 and / or PDE5) inhibitory action, pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin or heart, non-alcoholic steatohepatitis, diabetes Provided are compounds that can be useful as preventive and / or therapeutic agents for nephropathy and the like.

This application is based on Japanese Patent Application No. 2017-072396 filed in Japan, the contents of which are incorporated in full herein.

Claims

4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide;
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide; and
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3 , 2-d] pyrimidine-7-carboxamide or a salt thereof.
4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- {trans-4-[(N, N-dimethylglycyl) amino] cyclohexyl} -6-methyl-5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide;
4- (5- (Difluoromethyl) -2-{[1- (difluoromethyl) cyclopropyl] methoxy} phenyl) -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide; and
4- {2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl} -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo The compound or salt thereof according to claim 1, which is a compound selected from [3,2-d] pyrimidine-7-carboxamide or a salt thereof.
A medicament comprising the compound according to claim 1 or a salt thereof.
The pharmaceutical according to claim 3, which is a PDE4 / 5 inhibitor.
The medicament according to claim 3, which is a preventive or therapeutic agent for pulmonary hypertension and / or pulmonary fibrosis.
4. The medicine according to claim 3, which is a preventive or therapeutic agent for nonalcoholic steatohepatitis and / or diabetic nephropathy.
The medicament according to claim 3, which is a prophylactic or therapeutic agent for fibrosis in the liver, kidney, skin or heart.
The compound or a salt thereof according to claim 1, for use in the prevention or treatment of pulmonary hypertension and / or pulmonary fibrosis.
The compound according to claim 1 or a salt thereof for use in the prevention or treatment of nonalcoholic steatohepatitis and / or diabetic nephropathy.
The compound according to claim 1 or a salt thereof for use in the prevention or treatment of fibrosis in the liver, kidney, skin or heart.
A method for inhibiting PDE4 / 5 in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
A method for preventing or treating pulmonary hypertension and / or pulmonary fibrosis in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
A method for preventing or treating nonalcoholic steatohepatitis and / or diabetic nephropathy in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
A method for preventing or treating fibrosis in the liver, kidney, skin or heart of a mammal, comprising administering an effective amount of the compound or salt thereof according to claim 1 to the mammal.
Use of the compound according to claim 1 or a salt thereof for producing a preventive or therapeutic agent for pulmonary hypertension and / or pulmonary fibrosis.
Use of the compound according to claim 1 or a salt thereof for producing a preventive or therapeutic agent for non-alcoholic steatohepatitis and / or diabetic nephropathy.
Use of the compound according to claim 1 or a salt thereof for producing a prophylactic or therapeutic agent for fibrosis in the liver, kidney, skin or heart.